Case Illustration Seminar
Gastroesophageal reflux disease
Justin Wu
Professor, Department of Medicine & Therapeutics
Assistant Dean (Clinical), Faculty of Medicine
The Chinese University of Hong Kong
Case 1• A 35 y.o. man presents with frequent heartburn
and acid regurgitation for several years. The
symptoms respond to proton pump inhibitor but
they relapse after cessation of PPI. Endoscopy is
normal and H. pylori testing is negative. What is
your diagnosis?
1. Gastroesophageal reflux disease
2. Functional dyspepsia
3. No diagnosis
Esophagus
Stomach
Lower esophageal sphincter
What is GERD?
Gastric acid
Troublesome symptoms
Complications
Typical reflux symptoms
• Acid regurgitation
• Heartburn
• Mostly occur after 1-3 hours after meal
• Occasionally aggravated by lying down,
bending forward and straining
• Belching is NOT a reflux symptom
Spectrum of GERD
Esophageal acid exposure
Reflux esophagitis
Barrett’s esophagus / Adenocarcinoma
Peptic stricture
Endoscopy negative GERD
GERD: An emerging disease in HK
18
15.4
10.4 10.1
8.59.7
7.1
2.3
3.84.9 5.2 5.4 5.6 5.8
0
2
4
6
8
10
12
14
16
18
20
1996 1997 1998 1999 2000 2001 2002
All H. pylori peptic ulcer
All GERD
Annual incidence
/10,000 persons 36,759 endoscopy records
32,807 records analyzable
Wu et al. DDW 2006
GERD: Symptom based diagnosis
Reflux symptom
Alarm symptom
Empirical PPI (PPI Test)
No
Endoscopy
Yes
Dent et al. Genval Report. Gut 1999
Good response
GERD
No response
Symptom relapse
Lower pretest probability of PPI test in Asia
At least weekly reflux symptoms based
on questionnaire / telephone survey
3%
17%
6%
3%2% 2%
4%
7%
5%
18%
8%
15%
8%
10%
18%
15%17%
13%
28%
20%20%
0%
5%
10%
15%
20%
25%
30%
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Iran
Iran
Isra
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UK
Finla
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SAU
SAU
SA
Prevalence
460 patients with frequent heartburn/ acid regurgitation as dominant
complaint recruited for OGD (NSAID use and alarm symptoms excluded)
Is symptom based diagnosis reliable?
218 (48%)
148 (32%)
82 (18%)
OGD neg, no response to PPI
OGD neg, clinical response to PPI
Reflux esophagitis
Peptic ulcer (95% H. pylori
positive)
Predictors of PU
Male, H. pylori, age>60
Wu et al. Gastrointest Endosc 2002
Empirical PPI based on reflux symptom may not be
appropriate in population with high prevalence of H. pylori
Case 1• A 35 y.o. man presents with frequent heartburn
and acid regurgitation for several years. The
symptoms respond to proton pump inhibitor but
they relapse after cessation of PPI. Endoscopy is
normal and H. pylori testing is negative. What is
your diagnosis?
1. Gastroesophageal reflux disease
2. Functional dyspepsia
3. No diagnosis
Case 2
• A 35 y.o. male presents with daily reflux
symptoms for years. OGD shows no esophagitis.
The symptoms persist despite successful H.
pylori eradication but they subside after a course
of Lansoprazole. What is your recommendation?
1.Off all medication
2.Step down to famotidine for long-term treatment
3.Continue Lansoprazole
H. pylori eradication cannot cure GERD
X
121086420
1.0
.9
.8
.7
.6
.5
.4
.3
.2
.1
0.0
Probability of treatment failure
Months
Duration of follow up
Eradication group, 43.2% (95% CI: 29.9-56.5%)
P=0.043, log rank testPlacebo group, 21.1%
(95% CI: 9.9-32.3%)
Wu. Gut 2004
H. pylori eradication leads to more difficult control of GERD
104 GERD patients randomized to H. pylori
eradication or placebo followed by PPI treatment
GERD is a relapsing disorder
Lundell. Gut 1999
Symptom remission rate after PPI withdrawn (%)
Objectives of treatment
1. Relieve symptom
2. Heal esophagitis
3. Prevent complication
Long-term treatment required
More demanding on acid suppression than
peptic ulcer
EVIDENCE-BASED LIFESTYLE MODIFICATIONS
LIFESTYLE FACTORS THAT MAY CONTRIBUTE TO GERD
• Weight loss
• Head-of-bed elevation
• Avoid night meals
• Alcohol
• Smoking
• Dietary intake(e.g. chocolate, fatty foods, citrus)
Kaltenbach et al. Arch Intern Med. 2006
How useful is lifestyle modification?
There is little clinical evidence that avoidance of
alcohol, smoking, or dietary factors improves
symptoms
PPI Vs H2RA for 4-8 week treatment of esophagitis
26 trials (N=4064)
RR:0.47 (95% CI: 0.41-0.53)
NNT: 3 (95% CI: 2.8-3.6)
Cochrane Database Systemic Review 2004
1st line treatment Step up / down therapy
NICE (UK) PPI Low dose / on-demand PPI
ACG (US) PPI (H2RA for
milder GERD)
Titrate PPI dose for symptom
control
Genval PPI (strongly
preferred) or
H2RA
Titrate PPI dose for symptom
control; step down to H2RA
after low-dose PPI
Asia-Pacific PPI On-demand PPI
Canadian PPI (preferred) or
H2RA
PPI or H2RA for symptom
control
Australian PPI On-demand PPI
PPI is the gold standard treatment for GERD
28 healthy male volunteers given ranitidine 150 mg
q.i.d. for 5 days with 24-hour intragastric pH
monitoring
Lachman L et al. Am J Gastroenterol. 2000
% time gastric pH>4: 54% →→→→ 30%
Rapid tolerance of H2RA Prokinetic
• No proven value for reflux symptoms or
esophagitis
Emerging issues of PPI use
• Fractures
• PPI-clopidogrel interactions
• Clostridium difficile colitis
• Community acquired pneumonia
• Non-Clostridium enteric infections
• ↓ Thyroxine absorption
• Hypomagnesaemia
• Case control study (13556 cases of hip fracture
Vs 135386 controls)
• Odds ratio
Standard dose: 1.44 (95% C.I.:1.30-1.59)
�1-year: 1.22 (95% C.I.: 1.15-1.30)
�2-year: 1.41 (95% C.I.:1.28-1.56)
�3-year: 1.54 (95% C.I.:1.37-1.73)
�4-year: 1.59 (95% C.I.: 1.39-1.80)
High dose: 2.65 (95% C.I.:1.80-3.90)
Yang et al. JAMA 2006
PPI and fractures
Food and Drug Administration, May 2010
• ↑ Risk in 6 out of 7 epidemiological studies
• Age >50, use >1 year, high dose
• ? Ca2+ malabsorption, ↑ Osteoclast activity
PPI & Fractures: Recommendations
• Identify high risk users
�Prior fractures
�Osteoporosis
�Age>50
�Female
• Avoid high dose PPI >1 year
• On demand PPI for mild disease
• Ca2+ and vitamin D suppl., bisphosphonate
PPI use and Clostridium difficile infection
• Pooled data of 39 observational studies (29 case-controls, 10 cohorts) with 313,000 cases of CDI
Pooled odds ratio (95% CI)
PPI alone 2.1 (1.7–2.7)
H2RA alone 1.5 (1.2–1.8)
PPI + antibiotic 3.9 (2.3–6.6)
Kwok et al. Am J Gastroenterol 2012.
How to minimize the risk of CDI?
• Identification of high-risk patients: old age,
immunosuppressant, cancer, IBD, renal
failure
• Temporary withdrawal of PPI
• Once-daily dosing
• Avoid high dose
• Indications of PPI should be justified
• Reflux are often episodic and self-limited
• Symptom-driven → patient friendly
• Better quality of life, less sick role
• Lower drug cost
• Avoid excessive chronic acid suppression
• PPI use in 33–50% of time; 70–93%
willing to continue treatment [Zacny et al. APT 2005]
Intermittent / on-demand PPI Step-down therapy: contraindications
• Severe esophagitis
• GERD complications: bleeding, peptic
stricture, Barrett’s esophagus
Case 2
• A 35 y.o. male presents with daily reflux
symptoms for years. OGD shows no esophagitis.
The symptoms persist despite successful H.
pylori eradication but they subside after a course
of Lansoprazole. What is your recommendation?
1.Off all medication
2.Step down to famotidine for long-term treatment
3.Continue Lansoprazole
New drugs
44 healthy volunteers randomized to Deslansoprazole 60
mg Vs Esomeprazole 40 mg
Pharmacodynamics: Deslansoprazole Vs Esomeprazole
Dual delayed-release delivery system (DDR™) Kukulka . Clin Exp Gastroenterol 2011
Higher serum concentration ⇒Superior acid suppression
Kukulka . Clin Exp Gastroenterol 2011
24-hour intragastric pH monitoring
Reflux inhibitors
• GABAB agonist
• Lesogabaran, arbaclofen
• ↓ transient LES relaxation and reflux
episodes
• Not superior to placebo for symptom
relief
Boeckxstaens et al. Gastroenterol 2010
Vakil et al. Am J Gastroenterol 2011
H+/K+ ATPase in active form
K+
H+
PPI acts slowly
K+K+
H+H+
Lumen
Parietal Cell
PPI
Irreversibly bind to active proton pump
X
Complete acid blockade after 3 days
ProtonationpH<pKa
Sulphenamide
H+/K+ ATPase (Proton pump)
K+
H+
Potassium-competitive acid blocker
K+K+
H+H+
Lumen
Parietal CellX
Complete acid blockade within 30 minutes
P-CAB
• Imidazopyridine compound
• No chemical conversion
• Reversible ionic bond with
proton pump
P-CAB has more potent inhibition of H+,K+ ATPase than PPI
% Inhibition of gastric H+,K+ ATPase
TAK-438 Lansoprazole
pH 6.5
pH 7.5
pH 6.5
pH 7.5
Hori et al. J Pharmacol Exp Ther 2011
Management of GERD
NERD or mild esophagitis
Infrequent mild reflux
Frequent moderate to severe reflux
Severe, complicated esophagitis
Regular PPI
Antireflux surgery
On-demand / intermittent
H2RA
On-demand / intermittent
PPI